Systematic Synthesis and Binding Study of HIV V3 Glycopeptides Reveal the Fine Epitopes of Several Broadly Neutralizing Antibodies

Jared Orwenyo, Hui Cai, John Giddens, Mohammed N. Amin, Christian Toonstra, Lai Xi Wang

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

A class of new glycan-reactive broadly neutralizing antibodies represented by PGT121, 10-1074, and PGT128 has recently been discovered that targets specific N-glycans and the peptide region around the V3 domain. However, the glycan specificity and fine epitopes of these bNAbs remain to be further defined. We report here a systematic chemoenzymatic synthesis of homogeneous V3 glycopeptides derived from the HIV-1 JR-FL strain carrying defined N-glycans at N332, N301, and N295 sites. Antibody binding studies revealed that both the nature and site of glycosylation in the context of the V3 domain were critical for high-affinity binding. It was found that antibody PGT128 exhibited specificity for high-mannose N-glycan with glycosylation site promiscuity, PGT121 showed binding specificity for glycopeptide carrying a sialylated N-glycan at N301 site, and 10-1074 was specific for glycopeptide carrying a high-mannose N-glycan at N332 site. The synthesis and binding studies permit a detailed assessment of the glycan specificity and the requirement of peptide in the context of antibody-antigen recognition. The identified glycopeptides can be used as potential templates for HIV vaccine design.

Original languageEnglish (US)
Pages (from-to)1566-1575
Number of pages10
JournalACS Chemical Biology
Volume12
Issue number6
DOIs
StatePublished - Jun 16 2017

Bibliographical note

Funding Information:
We thank members of the Wang lab for technical assistance and discussions. We also thank P. Bjorkman and her lab members for kindly providing PGT128, 10-1074 and corresponding Fab proteins. This work was supported by the National Institutes of Health (NIH grants R01AI113896).

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